Formation of chiral 4-chromanones using chiral pyrrolidines in the presence of ureas or thioureas

ABSTRACT

The present invention relates to a synthesis of chromanones or chromanes in a stereospecific matter in view of the 2-position in the chromanone or chromane ring. It has been found that this synthesis is particularly possible in the presence of a chiral compound of formula of a specific type and of at least one urea or thiourea.

TECHNICAL FIELD

The present invention relates to the field of the synthesis oftocopherols and tocotrienols.

BACKGROUND OF THE INVENTION

Chromane compounds represent an important class of chiral naturalproducts and bioactive compounds. An important class of chromanecompounds are vitamin E and its esters. Often vitamin E iscommercialized in the form of its esters because the latter show anenhanced stability.

On the one hand the typical technical synthesis of vitamin E leads tomixtures of isomers. On the other hand higher bioactivity (biopotency)has been shown to occur in general by tocopherols and tocotrienolshaving the R-configuration at the chiral centre situated next to theether atom in the ring of the molecule (indicated by * in the formulasused later on in the present document) (i.e. 2R-configuration), ascompared to the corresponding isomers having S-configuration.Particularly active are the isomers of tocopherols having the naturalconfiguration at all chiral centres, for example (R,R,R)-tocopherols, ashas been disclosed for example by H. Weiser et al. in J. Nutr. 1996,126(10), 2539-49. This leads to a strong desire for an efficient processfor separating the isomers. Hence, the isomer separation not only ofvitamin E, but also of their esters, particularly their acetates, aswell as of their precursors is of prime interest.

Separation of all the isomers by chromatographic methods is extremelydifficult and costly.

To overcome these inherent problems, it has been tried to offerstereospecific synthesis allowing the preferential formation of thedesired isomers only. However, these methods are very expensive, complexand/or exotic as compared to the traditional industrial synthesisleading to isomer mixtures.

Therefore, there exists a large interest in providing stereospecificsynthesis routes leading to the desired isomer.

Particular difficult is to achieve specifically the desired chirality atthe chiral carbon centre in the 2-position of the chromane ring.

A synthetic pathway for chromanes is via their correspondingchromanones. It is known from Kabbe and Heitzer, Synthesis 1978; (12):888-889 that α-tocopherol can be synthesized via α-tocotrienol from4-oxo-α-tocotrienol which is accessible from2-acetyl-3,5,6-trimethylhydroquinone and farnesylacetone in the presenceof pyrrolidine. However, this procedure leads to a racemic mixture inview of the configuration at the 2-position of the chromane respectivelychromanone ring.

SUMMARY OF THE INVENTION

Therefore, the problem to be solved by the present invention is to offera method for the synthesis of chromanones or chromanes, i.e. ofcompounds of formula (I) or (V) in a stereospecific matter in view ofthe 2-position in the chromanone or chromane ring.

Surprisingly, it has been found that a process for the manufacturingaccording to claim 1 is able to solve this problem.

It has been particularly found that the combination of a specific chiralcompound and at least one urea compound of formula (X-A) or at least onethiourea compound of formula (X-B) leads to the formation of the desiredproduct and a desired stereoselective formation. Particularly, thedesired isomer is formed in preference over the non-desired isomeryielding to an enantiomeric ratio being larger than zero, or a ratio of[2R]-stereoisomers to [2S]-stereoisomers being larger than one.

Further aspects of the invention are subject of further independentclaims. Particularly preferred embodiments are subject of dependentclaims.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the present invention relates to a process for themanufacturing of a compound of formula (I)

-   -   comprising the step of reacting compound of formula (II-A) and        compound of formula (II-B) in the presence of    -   at least one chiral compound of formula (II-C) and of    -   at least one urea compound of formula (X-A) or at least one        thiourea compound of formula (X-B)

-   -   wherein R¹, R³ and R⁴ are independently from each other hydrogen        or methyl groups;    -   R² and R^(2′) represents hydrogen or a phenol protection group;    -   R⁵ represents either a linear or branched completely saturated        C₆₋₂₅-alkyl group or a linear or branched C₆₋₂₅-alkyl group        comprising at least one carbon-carbon double bond;    -   Y¹ represents either CH₂Y² or

-   -   -   wherein R⁶ represents a linear or branched C₁₋₁₂-alkyl group            which optionally further comprises at least one aromatic            group and/or C═O and/or NH and/or NH₂ group;        -   Y² represents either OH or OR⁷ or NHR⁷ or NHCOOR⁷ or

-   -   -   wherein R⁷ represents either            -   a linear or branched C₁₋₁₂-alkyl group which optionally                further comprises at least one aromatic group and/or C═O                and/or NH and/or NH₂ group        -   or            -   an aryl group or a substituted aryl group or a                heteroaryl group or a substituted heteroaryl group

    -   and the dotted line(s) represents the bond(s) by which the        corresponding substituent is bound to the rest of formula        (II-C);

    -   and wherein * represents the chiral centre of the chiral isomer        of formula (I) and wherein

Z¹ represents either H or a group CH₂Z⁴ or an aryl group;

-   -   Z² represents either H or a group CH₂Z⁴ or an aryl group;    -   Z³ represents either H or a group CH₂Z⁴ or an aryl group;        -   wherein Z⁴ represents H or an C₁-C₆ alkyl group;    -   with the proviso that if Z¹ is different from H, that Z²        represents H.

The term “independently from each other” in this document means, in thecontext of substituents, moieties, or groups, that identicallydesignated substituents, moieties, or groups can occur simultaneouslywith a different meaning in the same molecule.

A “C_(x-y)-alkyl”, resp. “C_(x-y)-acyl” group, is an alkyl resp. an acylgroup comprising x to y carbon atoms, i.e. for example an C₁₋₃-alkylgroup, is an alkyl group comprising 1 to 3 carbon atoms. The alkyl resp.the acyl group can be linear or branched. For example —CH(CH₃)—CH₂—CH₃is considered as a C₄-alkyl group.

A “C_(x-y)-alkylene” group is an alkylene group comprising x to y carbonatoms, i.e., for example C₂-C₆ alkylene group is an alkyl groupcomprising 2 to 6 carbon atoms. The alkylene group can be linear orbranched. For example the group —CH(CH₃)—CH₂— is considered as aC₃-alkylene group.

The term “hydrogen” means in the present document H and not H₂.

The sign * in formulae of molecules represents in this document a chiralcentre in said molecule.

In the present document any single dotted line represents the bond bywhich a substituent is bound to the rest of a molecule.

The chirality of an individual chiral carbon centre is indicated by thelabel R or S according to the rules defined by R. S. Cahn, C. K. Ingoldand V. Prelog. This R/S-concept and rules for the determination of theabsolute configuration in stereochemistry is known to the person skilledin the art.

The residue R⁵ represents either a linear or branched completelysaturated C₆₋₂₅-alkyl group or a linear or branched C₆₋₂₅-alkyl groupcomprising at least one carbon-carbon double bond.

Preferably the group R⁵ is of formula (III).

In formula (III) m and p stand independently from each other for a valueof 0 to 5 provided that the sum of m and p is 1 to 5. Furthermore, thesubstructures in formula (III) represented by s1 and s2 can be in anysequence. The dotted line represents the bond by which the substituentof formula (III) is bound to the rest of the compound of formula (II-B)or formula (I). Furthermore, # represents a chiral centre, obviouslyexcept in case where said centre is linked to two methyl groups.

It is preferred that group R⁵ is of formula (III-x).

As mentioned above the substructures in formula (III) represented by s1and s2 can be in any sequence. It is, therefore, obvious that in casethat the terminal group is having the substructure s2, this terminalsubstructure has no chiral centre.

In one preferred embodiment m stands for 3 and p for 0.

In another preferred embodiment p stands for 3 and m for 0.

Therefore, R⁵ is preferably of formula (III-A), particularly (III-ARR),or (III-B).

Preferred are the following combinations of R¹, R³ and R⁴:

R¹=R³=R⁴=CH₃

or

R¹=R⁴=CH₃, R³=H

or

R¹=H, R³=R⁴=CH₃

or

R¹=R³=H, R⁴=CH₃

R² and R^(2′) represents either hydrogen or a phenol protection group.

A phenol protection group is a group which protects the phenolic group(OH in formula (I) or (II-A)) and can be deprotected easily, i.e. bystate-of-the-art methods, to the phenolic group again.

The phenol protection group forms with the rest of the molecule achemical functionality which is particularly selected from the groupconsisting of ester, ether or acetal. The protection group can be easilyremoved by standard methods known to the person skilled in the art.

In case where the phenol protection group forms with the rest of themolecule an ether, the substituent R² or R^(2′) is particularly a linearor branched C₁₋₁₀-alkyl or cycloalkyl or aralkyl group. Preferably thesubstituent R² or R^(2′) is a benzyl group or a substituted benzylgroup, particularly preferred a benzyl group.

In case where the phenol protection group forms with the rest of themolecule an ester, the ester is an ester of an organic or inorganicacid.

If the ester is an ester of an organic acid, the organic acid can be amonocarboxylic acid or a polycarboxylic acid, i.e. an acid having two ormore COOH-groups. Polycarboxylic acids are preferably malonic acid,succinic acid, glutaric acid, adipic acid, maleic acid or fumaric acid.

Preferably the organic acid is a monocarboxylic acid.

Hence, the substituent R² or R^(2′) is preferably an acyl group. Theacyl group is particularly a C₁₋₇-acyl, preferably acetyl,trifluoroacetyl, propionyl or benzoyl group, or a substituted benzoylgroup.

If the ester is an ester of an inorganic acid, the inorganic acid ispreferably nitric acid or a polyprotic acid, i.e. an acid able to donatemore than one proton per acid molecule, particularly selected from thegroup consisting of phosphoric acid, pyrophosphoric acid, phosphorousacid, sulphuric acid and sulphurous acid.

In case where the phenol protection group forms with the rest of themolecule an acetal, the substituent R² or R^(2′) is preferably

with n=0 or 1.

Hence, the acetals formed so are preferably methoxymethyl ether(MOM-ether), β-methoxyethoxymethyl ether (MEM-ether) ortetrahydropyranyl ether (THP-ether). The protection group can easily beremoved by acid.

The protecting group is introduced by reaction of the correspondingmolecule having an R² resp. R^(2′) being H with a protecting agent.

The protecting agents leading to the corresponding phenol protectiongroups are known to the person skilled in the art, as well as thechemical process and conditions for this reaction. If, for example, thephenol protection group forms with the rest of the molecule an ester,the suitable protecting agent is for example an acid, an anhydride or anacyl halide.

In the case that an ester is formed by the above reaction with theprotecting agent, and that said ester is an ester of an organicpolycarboxylic acid or an inorganic polyprotic acid, not necessarily allacid groups are esterified to qualify as protected in the sense of thisdocument. Preferable esters of inorganic polyprotic acids arephosphates.

It is preferred that the protection group R² resp. R^(2′) is a benzoylgroup or a C₁₋₄-acyl group, particularly acetyl or trifluoroacetylgroup. The molecules in which R² resp. R^(2′) represents an acyl group,particularly an acetyl group, can be easily prepared from thecorresponding unprotected molecule by esterification, respectively thephenolic compound can be obtained from the corresponding ester by esterhydrolysis.

It is important to realize that the step of reacting with the protectingagent can occur at different stages of manufacture of compound offormula (I) or of formula (V), the preparation of which is describedlater in this document in more detail, i.e. the reaction can occur forexample at the level of compound of formula (II-A) or before or afterpreparation of compound (I) or compound (V).

It is particularly preferred that R² and R^(2′) is H.

The process of the present invention comprises the steps of reactingcompound of formula (II-A) and compound of formula (II-B).

The corresponding compounds of (II-A) and compound of formula (II-B) areeasily accessible. For example compounds of (II-A) can be synthesizedfrom the method disclosed in G. Manecke, G. Bourwieg, Chem. Ber. 1962,95, 1413-1416.

The mentioned reaction between compound of formula (II-A) and compoundof formula (II-B) is done in the presence of at least one chiralcompound of formula (II-C) and of at least one urea compound of formula(X-A) or at least one thiourea compound of formula (X-B).

The group Y¹ represents either CH₂Y² or

R⁶ represents in first instance a linear or branched C₁₋₁₂-alkyl group.Particularly suitable linear or branched C₁₋₁₂-alkyl groups are methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,pentyl, hexyl, heptyl and octyl groups.

R⁶ represents in second instance a linear or branched C₁₋₁₂-alkyl groupwhich comprises further at least one aromatic group and/or C═O and/or NHand/or NH₂ group. Examples of suitable compounds of formula (II-C) forthis embodiment are

Y² represents either OH or OR⁷ or NHR⁷ or NHCOOR⁷ or

R⁷ represents in a first instance a linear or branched C₁₋₁₂-alkylgroup. Particularly suitable linear or branched C₁₋₁₂-alkyl groups aremethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl and octyl groups.

R⁷ represents in a second instance a linear or branched C₁₋₁₂-alkylgroup which further comprises at least one aromatic group and/or C═Oand/or NH and/or NH₂ group.

R⁷ represents in a third instance an aryl group or a substituted arylgroup or a heteroaryl group or a substituted heteroaryl group. The arylgroup or a substituted aryl group or a heteroaryl group or a substitutedheteroaryl group is particularly

It is preferred that the compound of formula (II-C) is selected from thegroup consisting of

The compounds of formula (II-B) can be synthesized from correspondingprecursors, for example the compound (E,E)-farnesylacetone fromnerolidol by a chain-elongation reaction, as described in WO2009/019132.

In one preferred embodiment the group R⁵ does not comprise any chiralcentres. The compound of formula (II-B) is preferred from the groupconsisting of (E)-6,10-dimethylundeca-5,9-dien-2-one,(5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one and(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,particularly (5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one.

When the group R⁵ comprises chiral centres, it is preferred that thecompound of formula (II-B) is in a form of pure chiral isomers.

This can be either achieved by stereospecific synthesis routes or byisolation of naturally occurring compounds or derived thereof or byseparation from a mixture of the chiral stereoisomers.

For example (6R,10R)-6,10,14-trimethylpentadecan-2-one can be obtainedfrom naturally occurring (R,R)-phytol by oxidation with NaIO₄ and acatalytic amount of RuCl₃ as disclosed by Thomas Eltz et al. in J. Chem.Ecol. (2010) 36:1322-1326.

In another preferred embodiment the compound of formula (II-B) is amethyl ketone having at least a carbon-carbon double bond in theγ,δ-position to the keto group. Preferably it is selected from the groupconsisting of 6-methylhept-5-en-2-one,(E)-6,10-dimethylundec-5-en-2-one, (Z)-6,10-dimethylundec-5-en-2-one,(E)-6,10-dimethylundeca-5,9-dien-2-one,(Z)-6,10-dimethylundeca-5,9-dien-2-one,(E)-6,10,14-trimethylpentadec-5-en-2-one,(Z)-6,10,14-trimethylpentadec-5-en-2-one;(5E,9E)-6,10,14-trimethylpentadeca-5,9-dien-2-one,(5E,9Z)-6,10,14-trimethylpentadeca-5,9-dien-2-one,(5Z,9E)-6,10,14-trimethylpentadeca-5,9-dien-2-one,(5Z,9Z)-6,10,14-trimethylpentadeca-5,9-dien-2-one;(E)-6,10,14-trimethylpentadeca-5,13-dien-2-one,(Z)-6,10,14-trimethylpentadeca-5,13-dien-2-one;(5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one,(5E,9Z)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one,(5Z,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one,(5Z,9Z)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one;(E)-6,10,14,18-tetramethylnonadec-5-en-2-one,(Z)-6,10,14,18-tetramethylnonadec-5-en-2-one;(5E,9E)-6,10,14,18-tetramethylnonadeca-5,9-dien-2-one,(5E,9Z)-6,10,14,18-tetramethylnonadeca-5,9-dien-2-one,(5Z,9E)-6,10,14,18-tetramethylnonadeca-5,9-dien-2-one,(5Z,9Z)-6,10,14,18-tetramethylnonadeca-5,9-dien-2-one;(5E,13E)-6,10,14,18-tetramethylnonadeca-5,13-dien-2-one,(5E,13Z)-6,10,14,18-tetramethylnonadeca-5,13-dien-2-one,(5Z,13E)-6,10,14,18-tetramethylnonadeca-5,13-dien-2-one,(5Z,13Z)-6,10,14,18-tetramethylnonadeca-5,13-dien-2-one;(E)-6,10,14,18-tetramethylnonadeca-5,17-dien-2-one,(Z)-6,10,14,18-tetramethylnonadeca-5,17-dien-2-one;(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5E,9E,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5E,9Z,13E)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5E,9Z,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5Z,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5Z,9E,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5Z,9Z,13E)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5Z,9Z,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one;(5E,13E)-6,10,14,18-tetramethylnonadeca-5,13,17-trien-2-one,(5E,13Z)-6,10,14,18-tetramethylnonadeca-5,13,17-trien-2-one,(5Z,13E)-6,10,14,18-tetramethylnonadeca-5,13,17-trien-2-one,(5Z,13Z)-6,10,14,18-tetramethylnonadeca-5,13,17-trien-2-one;(5E,9E)-6,10,14,18-tetramethylnonadeca-5,9,17-trien-2-one,(5E,9Z)-6,10,14,18-tetramethylnonadeca-5,9,17-trien-2-one,(5Z,9E)-6,10,14,18-tetramethylnonadeca-5,9,17-trien-2-one,(5Z,9Z)-6,10,14,18-tetramethylnonadeca-5,9,17-trien-2-one;(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5E,9E,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5E,9Z,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5E,9Z,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(ZE,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5Z,9E,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5Z,9Z,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5Z,9Z,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one.

In case there are chiral centres in the group R⁵, particularly if R⁵ hasthe formula (III-ARR), the corresponding compounds of formula (II-B) canbe prepared by asymmetrically hydrogenating olefinic unsaturatedprecursors thereof using chiral iridium complexes as disclosed in WO2006/066863 A1 and WO 2012/152779 A1 the entire content of which ishereby incorporated by reference.

In case the compounds just mentioned have chiral carbon centre(s) it ispreferred that said chiral centre(s) has/have the configuration asindicated in formula (III-x).

Preferably the compound of formula (II-B) in this embodiment is(E)-6,10-dimethylundec-5,9-dien-2-one (geranyl acetone) or(Z)-6,10-dimethylundec-5,9-dien-2-one (neryl acetone) or(5E,9E)-6,10,14-trimethylpentadeca-5,9-dien-2-one (E,E-farnesyl acetone)or (5Z,9Z)-6,10,14-trimethylpentadeca-5,9-dien-2-one (Z,Z-farnesylacetone) or (E)-6,10-dimethylundec-5-en-2-one or(Z)-6,10-dimethylundec-5-en-2-one or(E)-6,10,14-trimethylpentadec-5-en-2-one or(Z)-6,10,14-trimethylpentadec-5-en-2-one, preferably geranyl acetone orE,E-farnesyl acetone or (Z)-6,10-dimethylundec-5-en-2-one or(Z)-6,10,14-trimethylpentadec-5-en-2-one, more preferably geranylacetone or E,E-farnesyl acetone.

More preferred the compound of formula (II-B) is6,10-dimethylundecan-2-one or 6,10,14-trimethylpentadecan-2-one.

Most preferred the compound of formula (II-B) is either(6R),10-dimethylundecan-2-one or (6R,10R),14-trimethylpentadecan-2-one.

It is more preferred that the compound of formula (II-C) is selectedfrom the group consisting of

The process of the present invention comprises the steps of reactingcompound of formula (II-A) and compound of formula (II-B) in thepresence of at least one chiral compound of formula (II-C) and of atleast one urea compound of formula (X-A) or at least one thioureacompound of formula (X-B).

For the sake of clarity, it is stressed that substituents having thesame label in the same formula represent in the present application thesame group, meaning that in formula (X-A) and (X-B) the two groups Z¹are identical.

In those formulae Z¹ represents either H or a group CH₂Z⁴ or an arylgroup and Z² represents either H or a group CH₂Z⁴ or an aryl group andZ³ represents either H or a group CH₂Z⁴ or an aryl group, wherein Z⁴represents H or an C₁-C₆ alkyl group, with the proviso that if Z¹ isdifferent from H, that Z² represents H.

In other words, it is important to realize that except for the case ofurea and thiourea (Z¹=Z²=Z³=H), all suitable ureas or thioureas havenecessarily the structural element of formula (XI-a1) or (XI-a2) or(XI-b1) or (XI-b2) in common.

Furthermore, in the structures of (XI-a1), (XI-a2), (X-I-b1) and (XI-b2)the carbon(s) (indicated by C) attached to the nitrogen atom is either aCH₂ carbon atom or an aromatic carbon atom.

The aryl group in Z¹ or Z² or Z³ is preferably a group of formula (XII)

-   -   wherein Z⁵ is a C₁-C₆ alkyl group or a CF₃ group and n stands        for 0 or 1 or 2 or 3.

Said group of formula (XII) has, hence, either no or 1 or 2 or 3 groupsZ⁵ attached to the phenyl ring.

In case of two groups Z⁵ attached they are preferably attached in themeta positions in view of the binding site.

In case of three groups Z⁵ attached they are preferably attached in theortho positions and the para position in view of the binding site.

In a preferred embodiment the urea compound of formula (X-A) is aselected from the group consisting of urea, 1,3-dimethylurea,1,3-diethylurea, 1,1,3-trimethylurea, 1,1,3-triethylurea,1,3-diphenylurea and 1,3-bis(3,5-bis(tri-fluoromethyl)phenyl)urea.

In a preferred embodiment the thiourea compound of formula (X-B) is aselected from the group consisting of thiourea, 1,3-dimethylthiourea,1,3-diethylthiourea, 1,1,3-trimethylthiourea, 1,1,3-triethylthiourea,1,3-diphenylthiourea and1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea.

More preferred urea compound of formula (X-A) or thiourea compound offormula (X-B) are either selected from the group consisting of urea,1,3-dimethylurea, 1,1,3-trimethylurea and 1,3-diphenylurea or of thegroup consisting of thiourea, 1,3-diphenylthiourea and1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea.

The compounds of formula (II-C) are chiral compounds. The compounds areeither used directly as pure stereoisomers or separated by knowntechniques into the R- and the S-stereoisomer prior to the use for thepresent invention.

It has been found that the isomer shown in formula (II-C) yieldspreferentially the isomers of compound of formula (I), respectively offormula (V), showing the R-configuration at the chiral centre indicatedby *.

Therefore, it has been found that the chirality of the compound offormula (II-C) has an important effect on the chirality of the compoundbeing formed, i.e. on compound of formula (I) or of formula (V).

Hence, the isomer having the R-configuration at the chiral centre markedby * in formula (I) is preferentially formed in respect to thecorresponding isomer having the S-configuration at said chiral centre bythe above process.

On the other hand, it has been found that when using the stereoisomersshown in formula (II-C′) instead of compounds of formula (II-C)preferentially the isomers of compound of formula (I) resp. formula (V)showing the S-configuration at the chiral centre indicated by * areobtained.

Compound of formula (II-A) and compound of formula (II-B) are reacted inthe presence of at least one chiral compound of formula (II-C) and of atleast one urea compound of formula (X-A) or at least one thioureacompound of formula (X-B).

It is preferred that this reaction occurs in an organic solvent. In oneembodiment the reaction is undertaken in an organic solvent which is ahydrocarbon, preferably in an aromatic hydrocarbon, particularly intoluene, particularly at a temperature of preferably between 80° C. and150° C., more preferably of between 90° C. and 140° C., most preferablyat a temperature of between 100 and 110° C. at ambient pressure. It ispreferred that the reaction temperature is about 5 to 10° C. below theboiling point of the solvent.

In another embodiment the reaction is undertaken in an organic polarsolvent which is selected from the group consisting of alcohols, ethers,esters, carbonitriles, halogenated hydrocarbons and lactams.Particularly suitable polar solvents are acetonitrile, ethyl acetate,methanol, ethanol, dichloromethane, tetrahydrofuran (THF),N-methylpyrrolidone (NMP), 1,2-dichloroethane, 2,2,2- and isopropanol.

Furthermore, it has been shown that the amount of organic solvent ispreferably chosen so that at least a 4% by weight solution of compoundof formula (II-A) is obtained. In a preferred embodiment the weightratio between compound of formula (II-A) and organic solvent is between2:98 and 80:20, particularly between 3:97 and 50:50, preferably between4:96 and 30:70.

It has been found that the lower the temperature for the reaction ofcompound of formula (II-A) and compound of formula (II-B) is, the higherthe chiral purity of the compound of formula (I) resp. (V) in view ofchirality at the chiral centre indicated by * is. This chiral purity isexpressed by the enantiomeric excess (ee) being determined by theabsolute value of the difference of amounts of the R and S isomersdivided by the sum of amounts of both isomers: and is normally expressedin %.

${e\; e} = {{abs}\left( \frac{\lbrack R\rbrack - \lbrack S\rbrack}{\lbrack R\rbrack + \lbrack S\rbrack} \right)}$

We have been able to show that by using a reaction temperature of 0° C.the process has yielded in the formation of a product having anenantiomeric excess up to 40%, corresponding to a ratio of [R]/[S] of2.3. However, the reaction rate was rather low.

In view of reaction rate, it is preferred to have the reaction takingplace at higher temperatures higher than 0° C.

Furthermore, it might be helpful, particularly in the case where at lowreaction temperatures are used, to use molecular sieves in the reactionmedium.

The enantiomeric ratio can be increased further by optimizing thereaction conditions. The larger the enantiomeric ratio is the better.However, also at lower enantiomeric ratios the invention can beadvantageous as the complete separation of the isomers, such as bychromatography, particularly by chromatography using chiral stationaryphases, needs much less efforts as compared to a racemic mixture. Hence,the enantiomeric ratio should be at least 15%, preferably at least 20%,more preferably at least 25%.

In a further aspect, the invention relates to a process of manufacturinga compound of formula (V) comprising the steps

-   -   i) process of manufacturing of formula (I) as it has been        described in detail above;    -   ii) reducing of compound of formula (I)

The substituents R¹, R², R³, R⁴ and R⁵ are already discussed in detailabove.

Most preferably the chiral isomers of formula (V) are the isomersselected from the group consisting of

-   -   α-Tocopherol (R¹=R³=R⁴=CH₃, R⁵=(II-A), particularly (II-ARR),        R²=H),    -   β-Tocopherol (R¹=R⁴=CH₃, R³=H, R⁵=(II-A), particularly (II-ARR),        R²=H),    -   γ-Tocopherol (R¹=H, R³=R⁴=CH₃, R⁵=(II-A), particularly (II-ARR),        R²=H),    -   δ-Tocopherol (R¹=R³=H, R⁴=CH₃, R⁵=(II-A), particularly (II-ARR),        R²=H),    -   α-Tocotrienol (R¹=R³=R⁴=CH₃, R⁵=(II-B), R²=H),    -   β-Tocotrienol (R¹=R⁴=CH₃, R³=H, R⁵=(II-B), R²=H),    -   γ-Tocotrienol (R¹=H, R³=R⁴=CH₃, R⁵=(II-B), R²=H),    -   δ-Tocotrienol (R¹=R³=H, R⁴=CH₃, R⁵=(II-B), R²=H),        and the esters, particularly the acetates (R²=COCH₃), or        phosphates thereof.

Particularly preferred compounds of formula (V) are esters of organicand inorganic acids. Examples of esters of organic acids are acetate andsuccinate esters, esters of inorganic esters are tocopheryl phosphates,ditocopheryl phosphates, particularly α-tocopheryl phosphate andα-ditocopheryl phosphate.

Most preferred compounds of formula (V) are tocopherols and tocopherylacetates.

Most preferred compounds of formula (V) are tocopherols and tocopherylacetates.

The reduction in step ii) can be made by different ways. Typically it isreduced by using a reduction means.

Preferably the reduction is made by metallic zinc in the presence of anacid or an acid mixture, for example as disclosed for in U.S. Pat. No.6,096,907 or EP 0 989 126 the whole disclosure of which is incorporatedherein by reference.

The reduction step ii) is typically done in stirred vessel under inertatmosphere. It is further preferred that the step ii) is done at atemperature in the range of 30 to 90° C., particularly between 40 and65° C.

After completion of the reaction the compound of formula (V) ispurified, particularly by means of extraction.

It has been observed that the reduction of compound of formula (I) tocompound of formula (V) does not modify the chirality of the chiralcentre indicated by * in the formulae (I) resp. (V).

It has been found that the isomer shown in formula (II-C) yieldspreferentially the isomers of compound of formula (I), respectively offormula (V), showing the R-configuration at the chiral centre indicatedby *.

Hence, the isomer having the R-configuration at the chiral centre markedby * in formula (V) is preferentially formed in respect to thecorresponding isomer having the S-configuration at said chiral centre.

On the other hand, it has been found that when using the stereoisomersshown in formula (II-C′) instead of compounds of formula (II-C)preferentially the isomers of compound of formula (I) resp. formula (V)showing the S-configuration at the chiral centre indicated by * areobtained.

In a further aspect, the invention relates to a composition comprising

-   -   a) at least one compound of formula (II-A) and    -   b) at least one ketone of formula (II-B) and    -   c) at least one chiral compound of formula (II-C) and    -   d) at least one urea compound of formula (X-A) or at least one        thiourea compound of formula (X-B)

The substituents R¹, R^(2′), R³, R⁴, R⁵, Y¹, Z¹, Z² and Z³ have alreadybeen discussed in detail above.

Furthermore, details for the compound of formula (II-A), for compound offormula (II-B), for compound of formula (X-A), for compound of formula(X-B) and for chiral compound of formula (II-C) as well their preferredembodiments and their ratios have been discussed in detail alreadyabove.

As described above this composition is very suitable for the synthesisof compound of formula (I) which can be transformed to compound offormula (V).

Therefore, a chiral compound of formula (II-C) can be used for thepreparation of tocopherols or tocotrienols as it also discussed in greatdetail above. This use particularly involves the use of a chiralcompound of formula (II-C) for the preparation of compound of formula(I) followed by transformation to compound of formula (V). When this useis made in the presence of at least one urea compound of formula (X-A)or at least one thiourea compound of formula (X-B) the formation of thestereoisomer of formula (I) resp. (V) having the R configuration at thechiral carbon centre marked by * in formula (I) resp. (V) is obtained inan excess related to the corresponding stereoisomer having theS-configuration.

The details for chiral compound of formula (II-C), for compound offormula (I), for formula (V) and for the urea compound of formula (X-A)or thiourea compound of formula (X-B) as well their preferredembodiments and their ratios have been discussed in detail alreadyabove.

Examples

The present invention is further illustrated by the followingexperiments.

Use of Additives

0.5 mmol of 2-acetyl-3,5,6-trimethylhydroquinone and 0.795 mmol of theadditive indicated in table 1 have been suspended in a 20 mL roundbottom flask equipped with a magnetic stirring bar, heating device,water and argon supply at 23° C. in 2.5 mL (23.47 mmol) toluene. Then0.514 mmol of E,E-farnesylacetone has been is added and finally 0.795mmol (S)-2-(methoxymethyl)pyrrolidine has been added. The reactionmixture has been stirred at 23° C. for the time indicated in table 1.When heated to 120° C. water is distilled off and the reaction mixturewas getting brown. After the indicated time at 120° C., the reactionmixture was cooled to 23° C. Then 1 mL of 2 N HCl has been added and themixture has been transferred to a separation funnel and was well shaken.The toluene phase was separated and washed with portions of 10 mL wateruntil a neutral water phase was obtained. The organic layers are driedover sodium sulfate, filtered and concentrated at 40° C. and 10 mbar.

The product formed and isolated by column chromatography on SiO₂ hasbeen identified to be6-hydroxy-2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-one:

¹H NMR (CDCl₃, 300 MHz) δ 1.30 (s, 3H); 1.51 (s, 6H); 1.52 (s, 3H);1.54-1.58 (m, 1H); 1.61 (d, J=0.9 Hz, 3H); 1.67-1.78 (m, 1H); 1.67-2.10(m, 10H); 2.08 (s, 3H); 2.16 (s, 3H); 2.48 (s, 3H); 2.51 (d, J=15.8 Hz,1H); 2.68 (d, J=15.8 Hz, 1H), 4.45 (s br, 1H); 4.99-5.05 (m, 3H) ppm.

¹³C NMR (CDCl₃, 75.5 MHz) δ 12.1; 12.8; 13.3; 15.9; 16.0; 17.7; 22.2;23.7; 25.1; 26.6; 26.8; 39.4; 39.7 (2C); 49.5; 79.4; 116.7; 120.4;123.5; 124.0; 124.1; 124.4; 131.3; 132.0; 135.1; 135.7; 145.8; 152.8;195.2 ppm.

Determination of enantiomeric ratio: HPLC, Chiralcel® OD-H, 250×4.6 mm,10 mL EtOH, 990 mL n-hexane, 1.0 mL/min; detection at 220 nm.

TABLE 1 Different additives. t_(23° C.) t_(120° C.) Yield¹ ee Additive[h] [h] [%] [R]:[S] [%] Ref. 1 none 20 1.5 2.2 50:50 0 Ref. 21,2-dimethylurea 17 24 0 —² —² Ref. 3 1,1,3,3-tetramethylurea 17 48 0 —²—² Ref. 4 1,3-dicyclohexylurea 17 24 0 —² —² Ref. 51,1,3,3-tetramethylthiourea 17 48 0 —² —² Ref. 61,3-dicyclohexylthiourea 17 24 0 —² —² 1 urea 16 24 16 63:37 26 21,3-dimethylurea 16 124 18 58:42 16 3 1,1,3-trimethylurea 16 124 9 61:3922 4 1,3-diphenylurea 0 17 2.6 61:39 22 5 thiourea 0 5 13 60:40 20 61,3-diphenylthiourea 0 14 3 62:38 24 7 1,3-bis(3,5-bis(trifluoromethyl)-0 14 2 70:30 40 phenyl)thiourea ¹yield relative to2-acetyl-3,5,6-trimethylhydroquinone ²as no reaction occurred (yield:0%) no measurements were possible

Conversion of Chromanones to Chromans

6-hydroxy-2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-onebeen transformed to α-tocotrienol by treatment with zinc dust andaqueous hydrochloric acid, as described in detail by Baldenius et al.,EP 0 989 126 A1:

6-Hydroxy-2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-one(5.0 mmol) (example 2) was dissolved under an argon atmosphere in 25 mLtoluene, and 25% aqueous HCl (41.7 mL, 340 mmol) was added. To thismechanically stirred two-phasic mixture zinc dust (65 mmol) was added insmall portions (ca. 0.5 g) during 4 h. Stirring was continued at 40° C.for 16 h and at 65° C. for 1 h. After completion of the reaction (TLCcontrol), the mixture was cooled to room temperature and filteredthrough a pad of Dicalite. The filter residue was washed with 100 mLn-heptane, and the combined filtrates washed with 50 mL water. Theorganic layer was dried over sodium sulfate, filtered, concentrated at40° C. and 10 mbar and dried for 2 h at 0.003 mbar at 23° C. The 2.22 gyellowish-brown oil was purified by column chromatography (100 g SiO₂silica gel 60, n-hexane/EtOAc 9:1). After evaporation (40° C./20 mbar)and drying (0.021 mbar/23° C.) α-tocotrienol was obtained as ayellowish-brown oil (1.291 g, purity 93.9 wt %, yield 57%).

The compound obtained showed identical retention time in comparison toan authentic sample of natural (R,E,E)-α-tocotrienol, and the valuesobtained by measuring the ¹H NMR (CDCl₃, 300 MHz) were identical withthe values for α-tocotrienol, as for example reported by P. Schudel etal., Helv. Chim. Acta 1963, 46, 2517-2526.

Determination of enantiomeric ratio: HPLC, Chiralcel® OD-H, 250×4.6 mm,0.5% EtOH in n-hexane, 1.0 mL/min; detection at 220 nm.

1. Process for the manufacturing of compound of formula (I)

comprising the step of reacting compound of formula (II-A) and compoundof formula (II-B) in the presence of at least one chiral compound offormula (II-C) and of at least one urea compound of formula (X-A) or atleast one thiourea compound of formula (X-B)

wherein R¹, R³ and R⁴ are independently from each other hydrogen ormethyl groups; R² and R^(2′) represents hydrogen or a phenol protectiongroup; R⁵ represents either a linear or branched completely saturatedC₆₋₂₅-alkyl group or a linear or branched C₆₋₂₅-alkyl group comprisingat least one carbon-carbon double bond; Y¹ represents either CH₂Y² or

wherein R⁶ represents a linear or branched C₁₋₁₂-alkyl group whichoptionally further comprises at least one aromatic group and/or C═Oand/or NH and/or NH₂ group; Y² represents either OH or OR⁷ or NHR⁷ orNHCOOR⁷ or

wherein R⁷ represents either a linear or branched C₁₋₁₂-alkyl groupwhich optionally further comprises at least one aromatic group and/orC═O and/or NH and/or NH₂ group or an aryl group or a substituted arylgroup or a heteroaryl group or a substituted heteroaryl group and thedotted line(s) represents the bond(s) by which the correspondingsubstituent is bound to the rest of formula (II-C); and wherein *represents the chiral centre of the chiral isomer of formula (I); andwherein Z¹ represents either H or a group CH₂Z⁴ or an aryl group; Z²represents either H or a group CH₂Z⁴ or an aryl group; Z³ representseither H or a group CH₂Z⁴ or an aryl group; wherein Z⁴ represents H oran C₁-C₆ alkyl group; with the proviso that if Z¹ is different from H,that Z² represents H.
 2. Process according to claim 1 wherein R⁵ is offormula (III)

wherein m and p stand independently from each other for a value of 0 to5 provided that the sum of m and p is 1 to 5, and where thesubstructures in formula (III) represented by s1 and s2 can be in anysequence; and the dotted line represents the bond by which thesubstituent of formula (III) is bound to the rest of formula (II-B) orformula (I); and wherein # represents a chiral centre, obviously exceptin case where said centre is linked to two methyl groups.
 3. Processaccording to claim 1 wherein R¹=R³=R⁴=CH₃ or R¹=R⁴=CH₃, R³=H or R¹=H,R³=R⁴=CH₃ or R¹=R³=H, R⁴=CH₃.
 4. Process according to claim 1 whereinformula (II-C) is selected from the group consisting of


5. Process according to claim 1 wherein the urea compound of formula(X-A) is a selected from the group consisting of urea, 1,3-dimethylurea,1,3-diethylurea, 1,1,3-trimethylurea, 1,1,3-triethylurea,1,3-diphenylurea and 1,3-bis(3,5-bis(trifluoromethyl)phenyl)urea. 6.Process according to claim 1 wherein the thiourea compound of formula(X-B) is a selected from the group consisting of thiourea,1,3-dimethylthiourea, 1,3-diethylthiourea, 1,1,3-trimethylthiourea,1,1,3-triethylthiourea, 1,3-diphenylthiourea and1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea.
 7. Process ofmanufacturing compound of formula (V) comprising the step of i) processof manufacturing of formula (I) according to claim 1; ii) reducing ofcompound of formula (I)


8. Process according to claim 1, wherein the isomer having theR-configuration at the chiral centre marked by * in formula (I) or (V)is preferentially formed in respect to the corresponding isomer havingthe S-configuration at said chiral centre.
 9. Composition comprising a)at least one compound of formula (II-A) and b) at least one ketone offormula (II-B) and c) at least one chiral compound of formula (II-C) andd) at least one urea compound of formula (X-A) or at least one thioureacompound of formula (X-B)

wherein R¹, R³ and R⁴ are independently from each other hydrogen ormethyl groups; R^(2′) represents hydrogen or a phenol protection group;R⁵ represents either a linear or branched completely saturatedC₆₋₂₅-alkyl group or a linear or branched C₆₋₂₅-alkyl group comprisingat least one carbon-carbon double bond; Y¹ represents either CH₂Y² or

wherein R⁶ represents a linear or branched C₁₋₁₂-alkyl group whichoptionally further comprises at least one aromatic group and/or C═Oand/or NH and/or NH₂ group; Y² represents either OH or OR⁷ or NHR⁷ orNHCOOR⁷ or

wherein R⁷ represents either a linear or branched C₁₋₁₂-alkyl groupwhich optionally further comprises at least one aromatic group and/orC═O and/or NH and/or NH₂ group or an aryl group or a substituted arylgroup or a heteroaryl group or a substituted heteroaryl group and thedotted line(s) represents the bond(s) by which the correspondingsubstituent is bound to the rest of formula (II-C); and wherein Z¹represents either H or a group CH₂Z⁴ or an aryl group; Z² representseither H or a group CH₂Z⁴ or an aryl group; Z³ represents either H or agroup CH₂Z⁴ or an aryl group; wherein Z⁴ represents H or an C₁-C₆ alkylgroup; with the proviso that if Z¹ is different from H, that Z²represents H.
 10. Composition according to claim 9, wherein R⁵ is offormula (III)

wherein m and p stand independently from each other for a value of 0 to5 provided that the sum of m and p is 1 to 5, and where thesubstructures in formula (III) represented by s1 and s2 can be in anysequence; and the dotted line represents the bond by which thesubstituent of formula (III) is bound to the rest of formula (II-B); andwherein # represents a chiral centre, obviously except in case wheresaid centre is linked to two methyl groups.
 11. Composition according toclaim 9 wherein R¹=R³=R⁴=CH₃ or R¹=R⁴=CH₃, R³=H or R¹═H, R³=R⁴=CH₃ orR¹=R³=H, R⁴=CH₃.
 12. Composition according to claim 9 wherein formula(II-C) is selected from the group consisting of


13. Composition according to claim 9 wherein the urea compound offormula (X-A) is a selected from the group consisting of urea,1,3-dimethylurea, 1,3-diethylurea, 1,1,3-trimethylurea,1,1,3-triethylurea, 1,3-diphenylurea and1,3-bis(3,5-bis(trifluoromethyl)phenyl)urea.
 14. Composition accordingto claim 9 wherein the thiourea compound of formula (X-B) is a selectedfrom the group consisting of thiourea, 1,3-dimethylthiourea,1,3-diethylthiourea, 1,1,3-trimethylthiourea, 1,1,3-triethylthiourea,1,3-diphenylthiourea and1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea.